Some bacteria such as Escherichia coli1-3, Salmonella3-9, Clostridum10-12 and Bifidobacterium13,14 are known to colonize and grow in tumor. In addition, recent studies showed that bacteria target primary tumors and metastasized tumors1-3. This feature has been used for vectors for tumor specific gene deliveryl15-18. Bacteria transformed with bioluminescent1-3 or fluorescent4,5 reporter gene were produced in order to monitor bacteria in vivo and the bacteria were used for tracking the movement thereof in model animals. As a result, the fates of the luminescent or fluorescent bacteria can be tracked noninvasively and reproducibly.
Abnormal supply of blood vessels found in tumors is a major factor for bacterial targeting18. Newly formed blood vessels in growing tumors are disorganized seriously and have imperfect endothelial lining and blind roof and result in insufficient blood stream and scant supplies of nutrients and oxygen19,20. It is presumed that poor nutrient delivery and oxygen deficiency induce hypoxic/anaerobic condition in tumor tissues and promote growth of obligatory and facultative anaerobic bacteria. According to previous report of the present inventors, facultative anaerobic bacteria including E. coli expressing lux operon (pLux) and Salmonella typhimurium having deficiency of ppGpp producing (ΔppGpp strain) target various solid tumor and the bacteria located preferentially in boundary region between peripheral proliferating region and central necrotic region2. The lux operon of Photobacterium leognathi encodes all proteins required to produce bioluminescence.
This document refers to several papers and patent documents and citations thereof are indicated throughout the document. The disclosures of the cited papers and patent documents are herein entirely incorporated by reference and thus the level of technical field to which the present invention belong and contents of the present invention are explained more definitely.